Lung cancer is the leading cause of cancer death worldwide leading to more deaths than breast, prostate, colon and pancreatic cancers combined. Lung cancer has a dismal 15% five year survival rate emphasizing need for novel therapy. Retinoblastoma (Rb) function is lost in >70% of lung cancers and loss of the Rb family member p130 portends a poor outcome. Since no methods exist to restore Rb family function, global gene expression analysis was performed on lungs with Rb family deficient epithelium to identify in vivo molecular targets with potential therapeutic utility. Data herein identify Pim-1 kinase as a novel druggable Rb family target expressed in lung cancer cells. The goal of this proposal is to test the hypothesis that combined Rb/p130 loss promotes lung cancer progression by enhancing Pim-1 mediated tumor cell survival. Three specific aims are proposed to directly test this hypothesis: 1) Determine the consequence of Pim-1 inhibition on lung cancer cell growth in vitro, 2) determine mechanisms underlying p130 suppression of Pim-1 expression, and 3) elucidate the prognostic significance of Pim-1 expression in human lung cancer specimens and determine efficacy of Pim-1 inhibition in vivo. Proposed studies will determine the effects of Pim-1 inhibition on lung cancer cell growth and define mechanisms underlying Pim-1 and Rb/p130 control of lung cancer progression. Our unique human lung cancer repository is used to determine Pim-1 function and define the prognostic and therapeutic potential of Pim-1 as a novel targeted therapy for lung cancer patients.